Identification of Novel Fragments Binding to the PDZ1-2 Domain of PSD-95

Inhibition of PSD-95 has emerged as a promising strategy for the treatment of ischemic stroke, as shown with peptide-based compounds that target the PDZ domains of PSD-95. In contrast, developing potent and drug-like small molecules against the PSD-95 PDZ domains has so far been unsuccessful. Here, we explore the druggability of the PSD-95 PDZ1-2 domain and use fragment screening to investigate if this protein is prone to binding small molecules. We screened 2500 fragments by fluorescence polarization (FP) and validated the hits by surface plasmon resonance (SPR), including an inhibition counter-test, and found four promising fragments. Three ligand efficient fragments were shown by ¹H,¹⁵N HSQC NMR to bind in the small hydrophobic P⁰ pockets of PDZ1-2, and one of them underwent structure-activity relationship (SAR) studies. Overall, we demonstrate that fragment screening can successfully be applied to PDZ1-2 of PSD-95 and disclose novel fragments that can serve as starting points for optimization towards small-molecule PDZ domain inhibitors.     

In Vivo Albumin-Binding of a C-Functionalized Cyclam Platform for 64Cu-PET/CT Imaging in Breast Cancer Model

An improved glucose-chelator-albumin bioconjugate (GluCAB) derivative, GluCAB-2^Mal, has been synthesized and studied for in vivo ⁶⁴Cu-PET/CT imaging in breast cancer mice models together with its first-generation analogue GluCAB-1^Mal. The radioligand works on the principle of tumor targeting through the enhanced permeability and retention (EPR) effect with a supportive role played by glucose metabolism. [⁶⁴Cu]Cu-GluCAB-2^Mal (99 % RCP) exhibited high serum stability with immediate binding to serum proteins. In vivo experiments for comparison between tumor targeting of [⁶⁴Cu]Cu-GluCAB-2^Mal and previous-generation [⁶⁴Cu]Cu-GluCAB-1^Mal encompassed microPET/CT imaging and biodistribution analysis in an allograft E0771 breast cancer mouse model. Tumor uptake of [⁶⁴Cu]Cu-GluCAB-2^Mal was clearly evident with twice as much accumulation as compared to its predecessor and a tumor/muscle ratio of up to 5 after 24 h. Further comparison indicated a decrease in liver accumulation for [⁶⁴Cu]Cu-Glu-CAB-2^Mal.     

Microstructure induced ultra-high energy storage density coupled with rapid discharge properties in lead-free Ba0.9Ca0.1Ti0.9Zr0.1O3–SrNb2O6 ceramics

Novel lead-free (1-x)Ba_0·9Ca_0·1Ti_0·9Zr_0·1O₃-xSrNb₂O₆ ceramics were synthesized via a two-step high energy ball milling process. The evolution of microstructural properties, phase transformation, and energy storage characteristics was comprehensively investigated to assess the applicability of material in multi-layered ceramic capacitors. The substitution of SrNb₂O₆ (SNO) in Ba_0·9Ca_0·1Ti_0·9Zr_0·1O₃ (BTCZ) has resulted in substantial improvement in materials density along with a small increase in the grain size of the synthesized ceramic. A thorough microstructural investigation indicates an excellent dispersibility and compatibility between BTCZ and SNO phases. With an increase in SNO substitution, a transition from typical ferroelectric to relaxor ferroelectric has been observed, which has led to a significantly slimmer ferroelectric loop along with frequency dispersive dielectric properties. The optimized composition (i.e., x = 0.10) exhibits an ultra-high recoverable energy density of 2.68 J/cm³ along with a moderately high energy efficiency of 83.4%. Further, SNO substituted samples have also shown an enhancement in breakdown strength. The improvement in energy storage performance and breakdown strength of SNO substituted BTCZ composites are mainly attributed to relatively homogeneous grain morphology, optimum grain size, microstructural density, and improved grain boundary interface.     

Structure-Activity Relationship Explorations and Discovery of a Potent Antagonist for the Free Fatty Acid Receptor 2

Free fatty acid receptor 2 (FFA2) is a sensor for short-chain fatty acids that has been identified as an interesting potential drug target for treatment of metabolic and inflammatory diseases. Although several ligand series are known for the receptor, there is still a need for improved compounds. One of the most potent and frequently used antagonists is the amide-substituted phenylbutanoic acid known as CATPB ( 1 ). We here report the structure-activity relationship exploration of this compound, leading to the identification of homologues with increased potency. The preferred compound 37 (TUG-1958) was found, besides improved potency, to have high solubility and favorable pharmacokinetic properties.     

Impact of an External Magnetic Field on Solitary Waves in Quantum Electron–Hole Plasmas of Semiconductors

Semiconductors - The propagation of solitary acoustic pulses in magnetized quantum electron–hole plasmas of semiconductors has been studied. The effects of an external magnetic field and...     

Effect of Nonuniform Magnetic Field That Magnetizes a Ferrite Film on the Measurement Accuracy for Characteristics of Spin Waves

Journal of Communications Technology and Electronics - A magnetic system is developed to generate a stationary uniform magnetic field in a relatively large region between the poles of a magnet that...     

Investigation of thermal residual stresses during laser ablation of tantalum carbide coated graphite substrates using micro-Raman spectroscopy and COMSOL multiphysics

Laser ablation of high-temperature ceramic coatings results in thermal residual stresses due to which the coatings fail by cracking and debonding. Hence, the measurement of such residual stresses during laser ablation process holds utmost importance from the view of performance of coatings in extreme conditions. The present research aims at investigating the effect of laser parameters such as laser pulse energy, scanning speed and line spacing on thermal residual stresses induced in tantalum carbide-coated graphite substrates. Residual stresses were measured using micro-Raman spectroscopy and correlated with Raman peak shifts. Transient thermal analysis was performed using COMSOL Multiphysics to model the single ablated track and residual stresses were reported at low, moderate and high pulse energy regimes. The results showed that the initial laser conditions caused higher tensile residual stresses. Moderate pulse energy regime comprised higher compressive residual stresses due to off centre overlapping of the laser pulses. Higher pulse energy (250 μJ), higher scanning speed (1000 mm/s) and moderate line spacing (20 μm) caused accumulation of tensile residual stresses during the final stage of laser ablation. The deviation of experimental residual stresses from COMSOL numerical model was attributed to unaccounted additional stresses induced during thermal spraying process and deformation potentials in the numerical model.     

Synthesis and Estimation of Some Surface-Active Compounds Derived from Fused Pyridine as Corrosion Inhibitors for Aluminum in Hydrochloric Acid Solutions

Protection of Metals and Physical Chemistry of Surfaces - Three nonionic surfactants molecules (NS) derived from a fused pyridine characterized by IR and 1HNMR spectra were synthesized and examined...     

Reduced Claudin-12 Expression Predicts Poor Prognosis in Cervical Cancer

Background: Within the claudin (CLDN) family, CLDN12 mRNA expression is altered in various types of cancer, but its clinicopathological relevance has yet to be established due to the absence of specific antibodies (Abs) with broad applications. Methods: We generated a monoclonal Ab (mAb) against human/mouse CLDN12 and verified its specificity. By performing immunohistochemical staining and semiquantification, we evaluated the relationship between CLDN12 expression and clinicopathological parameters in tissues from 138 cases of cervical cancer. Results: Western blot and immunohistochemical analyses revealed that the established mAb selectively recognized the CLDN12 protein. Twenty six of the 138 cases (18.8%) showed low CLDN12 expression, and the disease-specific survival (DSS) and recurrence-free survival rates were significantly decreased compared with those in the high CLDN12 expression group. We also demonstrated, via univariable and multivariable analyses, that the low CLDN12 expression represents a significant prognostic factor for the DSS of cervical cancer patients (HR 3.412, p = 0.002 and HR 2.615, p = 0.029, respectively). Conclusions: It can be concluded that a reduced CLDN12 expression predicts a poor outcome for cervical cancer. The novel anti-CLDN12 mAb could be a valuable tool to evaluate the biological relevance of the CLDN12 expression in diverse cancer types and other diseases.